Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma

Activation of beta -catenin/T cell factor (TCF) transcription as a result o f mutations in the adenomatous polyposis coli (APC) and/or beta -catenin ge nes occurs in the majority of colon tumors. An increasing number of genes, including c-myc and cyclin D1, have been implicated as targets of this path way. We now report that the dominant negative helix-loop-helix regulator Id 2 is also a target of the beta -catenin/TCF transcription pathway in colon adenocarcinoma. Investigation of the mechanism for the overexpression of Id 2 in colon carcinoma cells demonstrated that the Id2 promoter is activated, and the Id2 protein is up-regulated by beta -catenin. Conversely, reducing free beta -catenin blocked this induction of promoter activity. We have al so used an electrophoretic mobility shift assay and supershift to identify a motif in the Id2 promoter that binds to TCF4 protein. Site-directed mutag enesis of this motif abolished promoter reporter activity. Both transfectio n of Id2 into SW480 cells and induction of Id2 in HT29 colon cells was foun d to increase anchorage-independent survival of these cells. Growing eviden ce associates disruption to Id2 expression with tumorigenesis, and our find ings suggest that this dysregulation of Id2 expression is due to the activa tion of the beta -catenin/TCF pathway.